Oncotarget

Research Papers:

JWA down-regulates HER2 expression via c-Cbl and induces lapatinib resistance in human gastric cancer cells

Ling Ma, Weiyou Zhu, Qiang Wang, Fengming Yang, Jing Qian, Tongpeng Xu, Shouyu Wang, Jianwei Zhou and Yongqian Shu _

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Oncotarget. 2016; 7:71790-71801. https://doi.org/10.18632/oncotarget.12374

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Abstract

Ling Ma1, Weiyou Zhu1, Qiang Wang2, Fengming Yang1, Jing Qian1, Tongpeng Xu1, Shouyu Wang2, Jianwei Zhou2, Yongqian Shu1,3

1Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China

2Department of Molecular Cell Biology and Toxicology, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, People’s Republic of China

3Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, People’s Republic of China

Correspondence to:

Yongqian Shu, email: shuyongqian_njmu@163.com

Keywords: gastric cancer, lapatinib, HER2, JWA, c-Cbl

Received: April 24, 2016     Accepted: September 25, 2016     Published: September 30, 2016

ABSTRACT

Human epidermal growth factor receptor 2 (HER2) targeted therapy is currently considered as the standard treatment for HER2-positive advanced gastric cancer (GC). However, unsatisfactory results of recent phase III clinical trials involving lapatinib suggested biomarkers for selection of patients. The aim of this study was to identify JWA as a biomarker for lapatinib resistance in GC cells and elucidate the underlying mechanisms. Lapatinib was effective to the intrinsic cisplatin-resistant GC cells. JWA activation conferred lapatinib unresponsiveness, but reversed cisplatin resistance in GC cells. Whereas, deletion of JWA significantly restored lapatinib suppression on proliferation and lapatinib-induced apoptosis. JWA-induced down-regulation of HER2 and activation of ERK phosphorylation led to lapatinib resistance. Furthermore, c-Cbl represented a novel mechanism for HER2 degradation enhanced by JWA in GC cells. Taken together, JWA is a potential predictive marker for lapatinib resistance, targeting the patients that may benefit from lapatinib treatment in human GC.


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